Many biologically active macro-molecules, such as peptides/proteins and DNA, that are effective for gene therapy and a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. However, these molecules,are limited to parenteral administration due to their susceptibility to degradation in the gastrointestinal tract. Treatment for chronic illnesses or indications may require multiple injections per day over many days, or months. Patient compliance is usually poor. Therefore, it would be highly desirable to develop a system for the delivery of bioactive agents or drugs, in particular, polypeptide or protein drugs, at a controlled rate over a sustained period of time without the above mentioned problems. This system would help to optimize the therapeutic efficacy, minimize the side effects, and thereby improve patient compliance.
Drug loaded polymeric devices and dosage forms have been investigated for long term therapeutic treatment of different diseases. Because of strict regulatory compliance requirements such as biocompatibility, having a clearly defined degradation pathway, and safety of the degradation products, there are currently few synthetic or natural polymeric materials which can be used for the controlled delivery of drugs, including peptide and protein drugs.
In copending U.S. application Ser. No. 09/396,589, filed Sep. 15, 1999 which is a continuation in-part of U.S. application Ser. No. 09/164,865 filed Oct. 1, 1998 which in turn is a continuation-in-part of U.S. Pat. No. 6,004,573 which was filed on Oct. 3, 1997 and issued Dec. 21, 1999, there is disclosed a biodegradable reverse thermal gelation system comprising ABA- or BAB-type block copolymers having an average molecular weight of between about 2000 and 4990 consisting of about 51 to 83% by weight of a hydrophobic A polymer block comprising a biodegradable polyester, and about 17 to 49% by weight of a hydrophilic B polymer block consisting of polyethylene glycol (PEG). It is surprising that a block copolymer with such a large proportion of hydrophobic component would be water soluble below normal room temperatures, such as temperatures as low as 5° C.
The reverse thermal gelation system referenced in the preceding paragraph causes minimal toxicity and minimal mechanical irritation to the surrounding tissue because of the biocompatibility of the materials and pliability of the gel. In addition, these block copolymers biodegrade into non-toxic units. The drug release, gel strength, gelation temperature and degradation rate of each reverse gelation system can be controlled by proper design and preparation of the various copolymer blocks, namely, through modifications of the weight percent of A-blocks and B-blocks, the mole percentages of lactate and glycolate moieties making up the A-blocks, and the molecular weight and polydispersity of the ABA or BAB triblock copolymers. Drug release is also controllable through adjustment of the concentration of the block copolymer in the drug delivery liquid. It would be desirable to provide a biodegradable reverse gelation system having a gelation temperature within a desired range so that the system remains as a liquid at an ambient temperature, but become a gel at the body temperature of the object to which the drug is delivered. A reverse thermal gelation system with such gelation temperatures can be processed, formulated and dispensed at ambient temperatures, thereby significantly reducing manufacturing and handling costs. In addition, accidental gelation during application, e.g. gelation in the syringe during injection can be avoided. As discussed above, the gelation temperature of a reverse thermal gelation system may be modified by changing the chain length, the glycolide/lactide (G/L) mole ratio of the A-polymer block, the molecular weight of the B-polymer block, the weight ratio of A block and B block polymers, and by various additives. However, the above modifications also change the gel qualification as well as the gelation temperature. In addition, some additives may not be compatible with the drug to be delivered. Therefore, it is desirable to provide a reverse gelation system with adjustable gelation temperatures without changing its desirable gel qualities significantly.
It has been discovered that mixtures or blends of two or more tri-block polyester/polyethylene glycol(PEG)copolymers provides for improved reverse thermal gelation properties, such as an optimum gelation temperature, gel strength, degradation rate, and yet still maintains the desirable gel qualities. In addition, a combination of two or more different tri-block polyester/polyethylene glycol copolymers increases design flexibility. Such drug delivery systems have properties such as modulated drug release and modulated matrix erosion. These mixtures or blends of tri-block polyester\polyethylene glycol copolymers are very useful in drug delivery practice because they allow optimization to fit individual drug or patient's needs. Therefore, the present invention provides for a significant improvement in the art.